Stress resiliency and susceptibility: The neurocircuitry underlying the detrimental effects of chronic stress

Humans are remarkably resilient when confronted with tremendous amounts of stress and trauma. While most people are able to maintain balanced psychological and physical functioning, some people are vulnerable, or susceptible, to the negative biological, psychological, and social consequences of stress. The biological factors underlying susceptibility are unknown and likely intersect with an individual’s ability to cope, among other factors.

Emerging evidence from animal studies suggests there are distinct cellular and molecular adaptations that occur in response to stress to either promote resiliency or lead to susceptibility. The ventral striatum (vSTR) has been identified as a key brain region for regulating depression-related behaviors following chronic stress. In a recent study, Christoffel et al. elucidated the specific inputs to the vSTR mediating susceptibility to stress in mice following chronic social defeat stress (CSDS). CSDS is a well-validated model for studying the cellular and molecular underpinnings of stress-related psychiatric diseases in rodents.

The CSDS paradigm consists of pairing an experimental C57BL/6J mouse with an aggressive, CD-1 retired breeder mouse over the course of days in a cage. After each daily pairing, these mice are housed in the same cage, only separated by a partition with holes to allow for continuous ‘psychological’ stress for the experimental mouse from sensory interaction with the aggressor mouse. Following CSDS, the experimental mice are tested in the social interaction behavioral assay to assess the degree of social avoidance (i.e., anxiety and depression related behavior). The experimental mouse is placed into an open arena with the caged aggressor mouse and the amount of time spent socially interacting is recorded. Despite experiencing the same defeat stressor, experimental mice can be separated into ‘susceptible’ or ‘resilient’ groups to study the biological mechanisms contributing to these divergent phenotypes.

The authors used complementary approaches to identify and manipulate specific excitatory, glutamatergic inputs to the vSTR that mediate stress susceptibility. Projection-based viral targeting techniques revealed increased excitatory synaptic strength from the intralaminar (ILT) to the vSTR only in susceptible mice, whereas excitatory strength of the inputs to the vSTR from the prefrontal cortex (PFC) was similar between resilient and susceptible mice, suggesting enhanced ILT-vSTR signaling is relevant for stress-induced susceptibility.

Interestingly, inhibition of the ILT presynaptic inputs to the vSTR either by chronically inhibiting calcium release using viral-mediated expression of ‘tToxins’ or acutely by physiologically relevant optogenetic inhibition prevented stress-induced susceptibility, which was accompanied by reductions in excitatory postsynaptic currents (EPSCs) and the density of immature stubby dendritic spines of vSTR medium spiny neurons (MSNs).

In contrast, chronic inhibition of PFC-vSTR pathways further decreased stress-induced social interaction times and increased the density of stubby dendritic spines in the vSTR. However, acute, rapid optogenetic inhibition of this circuit had no effect on the susceptibility phenotype, suggesting sustained inhibition may be required, or other PFC efferents are responsible for promoting normal behavioral function (i.e., resiliency).

Human imaging findings indicate reduced vSTR response to various rewarding stimuli in individuals with major depressive disorder^1,2,3, which are further supported by studies using deep brain stimulation of the internal capsule (includes vSTR) to alleviate symptoms of depression⁴. The present findings suggest that distinct glutamatergic pathways converge on the vSTR reward circuitry to mediate stress-induced susceptibility or promote resiliency. Animal studies are beginning to shed light on how stress leads to alterations in activity of particular neural circuits that could be relevant for many psychiatric diseases.

Publication

1. Russo SJ et al. (2015) Excitatory transmission at thalamo-striatal synapses mediates susceptibility to social stress. Nature Neuroscience [Epub ahead of print]. doi: 10.1038/nn.4034

References

1. 1. Silbersweig DA et al. (2006) Lack of ventral striatal response to positive stimuli in depressed versus normal subjects. Am J Psychiatry 163:1784-1790. doi: 10.1176/ajp.2006.163.10.1784
2. 2. Fava M et al. (2009) Reduced caudate and nucleus accumbens response to rewards in unmedicated individuals with major depressive disorder. Am J Psychiatry 166:702-710. doi: 10.1176/appi.ajp.2008.08081201
3. 3. Strohle A et al. (2012) Hyporeactivity of ventral striatum towards incentive stimuli in unmedicated depressed patients normalizes after treatment with escitalopram. J Psychopharmacol 26:677-688. doi: 10.1177/0269881111416686
4. 4. Schlaepfer TE et al. (2010) Nucleus accumbens deep brain stimulation decreases ratings of depression and anxiety in treatment-resistant depression. Biol Psychiatry 67:110-116. doi: 10.1016/j.biopsych.2009.09.013